An efficient synthesis of new anthranilic acid derivatives led us to identify a series of potential anticancer agents. The in vitro anticancer screening performed by the NCl reveals that some esters of N-(2-(trifluoromethyl)pyridin-4-yl)anthranilic acid demonstrated interesting inhibitory properties against a wide array of human tumour cell lines. In particular, compounds 8a, 8b, 8c, 8d and 8e exhibited antiproliferative activity in nanomolar to low micromolar concentrations against most of the tested cell lines. On the basis of observed biological activities and compare analysis, putative cox-dependent/independent mechanisms responsible for antitumour activity were proposed.
Among the wide variety of synthetic compounds recognized as potential anticancer drugs, molecules based on the anthranilic acid scaffold have attracted great interest in recent years. Experimental and preclinical models demonstrated that a number of these compounds elicited outstanding anticancer activity through a range of biological activities implicated with the development and maintenance of tumour cells. In this context, several reports describing the antitumbur evaluation of anthranilate derivatives appeared in the recent literature. For example, Tranilast (FIG. 1) has been reported to exhibit antiproliferative activity against cultured leiomyoma cells, through the oppression of cyclin-dependent kinase (CDK) 2 activity. Yashiro et al. have described that Tranilast decreases the production of matrix metallo-proteinase-2 (MMP-2) and transforms the growth factor-a1 (TGF-a1) from fibroblasts, resulting in significant suppression of the invasion ability of gastric cancer cells. Farnesyl anthranilate has been shown to reveal tumour growth-suppressive action in experimental murine melanomas models, as a probable consequence of down regulation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity. Antitumour activity of the anthranilamide CI-1040 has been demonstrated in preclinical models, particularly for pancreas, colon, and breast cancers. The Cl-1040 activity has been correlated with its inhibition of mitogen-activated protein kinase (MAPk) cascade pathway. Moreover, the anthranilamide AAL993 has been described as a lead compound. (Cocco M T, Congiu C, Lilliu V Onnis V, Bioorg Med Chem Left, 2004, 23, 5787-5791, Cenzo Congiu, Maria Teresa Cocco, Lilliu V, Onnis V, J. Med. Chem. 2005, 48, 8245-8252).
However, the clinical efficacy for these anticancer agents is hindered by several limitations, such as poor water solubility, cardio toxicity, development of drug resistance and metabolic inactivation.
